NO309266B1 - Process for the preparation of optically enriched bupivacaine - Google Patents
Process for the preparation of optically enriched bupivacaine Download PDFInfo
- Publication number
- NO309266B1 NO309266B1 NO971903A NO971903A NO309266B1 NO 309266 B1 NO309266 B1 NO 309266B1 NO 971903 A NO971903 A NO 971903A NO 971903 A NO971903 A NO 971903A NO 309266 B1 NO309266 B1 NO 309266B1
- Authority
- NO
- Norway
- Prior art keywords
- solvent
- bupivacaine
- water
- levobupivacaine
- optically enriched
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 20
- LEBVLXFERQHONN-UHFFFAOYSA-N 1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide Chemical compound CCCCN1CCCCC1C(=O)NC1=C(C)C=CC=C1C LEBVLXFERQHONN-UHFFFAOYSA-N 0.000 title claims description 12
- 229960003150 bupivacaine Drugs 0.000 title claims description 10
- 238000002360 preparation method Methods 0.000 title description 2
- 239000002904 solvent Substances 0.000 claims abstract description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 12
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 6
- 239000011975 tartaric acid Substances 0.000 claims abstract description 6
- 235000002906 tartaric acid Nutrition 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 4
- 229960004288 levobupivacaine Drugs 0.000 claims description 7
- LEBVLXFERQHONN-INIZCTEOSA-N levobupivacaine Chemical compound CCCCN1CCCC[C@H]1C(=O)NC1=C(C)C=CC=C1C LEBVLXFERQHONN-INIZCTEOSA-N 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 4
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-LWMBPPNESA-N levotartaric acid Chemical group OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 claims description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 16
- 239000007787 solid Substances 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 229960001367 tartaric acid Drugs 0.000 description 5
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 4
- 239000012458 free base Substances 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- ZKMNUMMKYBVTFN-HNNXBMFYSA-N (S)-ropivacaine Chemical compound CCCN1CCCC[C@H]1C(=O)NC1=C(C)C=CC=C1C ZKMNUMMKYBVTFN-HNNXBMFYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 229960001050 bupivacaine hydrochloride Drugs 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- NTBIYBAYFBNTCD-UHFFFAOYSA-N dibenzoyl 2,3-dihydroxybutanedioate Chemical compound C=1C=CC=CC=1C(=O)OC(=O)C(O)C(O)C(=O)OC(=O)C1=CC=CC=C1 NTBIYBAYFBNTCD-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229960001464 levobupivacaine hydrochloride Drugs 0.000 description 1
- SIEYLFHKZGLBNX-NTISSMGPSA-N levobupivacaine hydrochloride (anhydrous) Chemical compound [Cl-].CCCC[NH+]1CCCC[C@H]1C(=O)NC1=C(C)C=CC=C1C SIEYLFHKZGLBNX-NTISSMGPSA-N 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 229960005015 local anesthetics Drugs 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 229960001549 ropivacaine Drugs 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- JCQBWMAWTUBARI-UHFFFAOYSA-N tert-butyl 3-ethenylpiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC(C=C)C1 JCQBWMAWTUBARI-UHFFFAOYSA-N 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Hydrogenated Pyridines (AREA)
- Peptides Or Proteins (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Investigating Or Analysing Biological Materials (AREA)
- Saccharide Compounds (AREA)
- Epoxy Compounds (AREA)
- Compounds Of Unknown Constitution (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Non-Silver Salt Photosensitive Materials And Non-Silver Salt Photography (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
Description
Foreliggende oppfinnelse vedrører fremgangsmåte for fremstilling av optisk anriket bupivacain som omfatter omsetning av bupivacain med et vinsyre-oppløsningsmiddel i et vannblandbart organisk løsningsmiddel. The present invention relates to a method for the production of optically enriched bupivacaine which comprises reacting bupivacaine with a tartaric acid solvent in a water-miscible organic solvent.
Bakgrunn for oppfinnelsen Background for the invention
Levobupivacain og analoger derav, så som ropivacain, er nyttige som lokale bedøvelsesmidler. Disse (S)-enantiomerer er av økende interesse som smertestillende midler med en høyere terapeutisk indeks enn de tilsvarende racemater. Kjente synteser har forskjellige ulemper. Levobupivacaine and its analogs, such as ropivacaine, are useful as local anesthetics. These (S)-enantiomers are of increasing interest as analgesics with a higher therapeutic index than the corresponding racemates. Known syntheses have various disadvantages.
Tullar et al, J.. Med. Chem. 14(9):891-2 (1971) og US-A-4.180.712 beskriver anvendelse av naturlig (R,R)-vinsyre som oppløsningsmiddel for adskillelse av levobupivacain og dets antipode . 2 mol ekvivalenter av basen benyttes pr. mol ekvivalent av det syreoppløsende midlet. For fremstilling av levobupivacain i industriell skala er dette upraktisk, siden (R)-bupivacain-(R.R)-tartratsalt krystalliserer seg først, noe som nødvendiggjør ytterligere bearbeiding og derfor senkning av den totale operasjonseffektivitet. Tullar et al, J.. Med. Chem. 14(9):891-2 (1971) and US-A-4,180,712 describe the use of natural (R,R)-tartaric acid as a solvent for the separation of levobupivacaine and its antipode. 2 mol equivalents of the base are used per mole equivalent of the acid dissolving agent. For the manufacture of levobupivacaine on an industrial scale, this is impractical, since the (R)-bupivacaine-(R.R)-tartrate salt crystallizes first, necessitating further processing and therefore lowering the overall operational efficiency.
Videre, for fraskillelse av levobupivacain fra dets antipode, gir fremgangsmåten som er beskrevet i teknikkens stand ikke reproduserbare utbytter av tartratsaltet, og det diastereomere overskuddet er variabelt. Furthermore, for the separation of levobupivacaine from its antipode, the procedure described in the prior art does not give reproducible yields of the tartrate salt, and the diastereomeric excess is variable.
Den kjente teknikk beskriver ikke en gjennomført reproduserbar fremgangsmåte. Eksperimentene slo feil noen ganger under anvendelse av de kjente betingelsene. The known technique does not describe a completely reproducible method. The experiments failed sometimes using the known conditions.
Federsel et al, Acta. Chem. Cand. B41:757-761 (1987), beskriver anvendelse av 0,52 ekvivalenter av oppløsningsmidlet dibenzoyltartrat for å komme frem til (S)-enantiomeren med formel I, når R=H. Kun krystallvann er til stede. Oppløsningsmidlet er kostbart. Federsel et al., Acta. Chem. Cand. B41:757-761 (1987), describes the use of 0.52 equivalents of the solvent dibenzoyl tartrate to arrive at the (S)-enantiomer of formula I, when R=H. Only crystal water is present. The solvent is expensive.
Oppsummering av oppfinnelsen Summary of the invention
Foreliggende oppfinnelse er basert på de overraskende oppdagelser at: The present invention is based on the surprising discoveries that:
1. Tilsetning av en lav konsentrasjon av vann, f.eks. i området 0,1-20%, til et alkoholisk oppløsningsmiddel, gir en mye mer reproduserbar oppløsning, tillater at fremgangsmåten utføres ved høyere konsentrasjoner (typisk 20 vekt/vol%), og gir levobupivacain-(S,S)-tartrat eller dets antipode ved høyere optisk renhet (typisk >98% diastereomert overskudd). 2. Anvendelse av mindre enn 0,5 mol-ekvivalenter av oppløsningsmidlet, fortrinnsvis 0,25 mol-ekvivalenter, gir levobupivacain-(S,S)-tartrat eller dets antipode ved høyere optisk renhet (typisk >98% diastereomert overskudd), og gir en mer effektiv anvendelse av oppløsningsmidlet. 1. Addition of a low concentration of water, e.g. in the range of 0.1-20%, to an alcoholic solvent, provides a much more reproducible solution, allows the process to be carried out at higher concentrations (typically 20 w/v%), and provides levobupivacaine-(S,S)-tartrate or its antipode at higher optical purity (typically >98% diastereomeric excess). 2. Use of less than 0.5 molar equivalents of the solvent, preferably 0.25 molar equivalents, yields levobupivacaine-(S,S)-tartrate or its antipode at higher optical purity (typically >98% diastereomeric excess), and provides a more efficient use of the solvent.
I tillegg: In addition:
3. Anvendelse av (S.S)-vinsyre, for å krystallisere ut levobupivacain-(S.S)-tartratsaltet først, er en mer effektiv fremangsmåte for fremstilling av 3. The use of (S.S)-tartaric acid, to crystallize out the levobupivacaine-(S.S)-tartrate salt first, is a more effective method for the preparation of
levobupivacain. levobupivacaine.
4. Levobupivacain-(S,S)-tartrat, eller dets antipode, kan omdannes direkte til hydrokloridsaltet. Dette står i kontrast til den kjente teknikk, som innebærer den mindre effektive fremgangsmåte å danne det ønskede hydroklorid fra fri base. 4. Levobupivacaine-(S,S)-tartrate, or its antipode, can be converted directly to the hydrochloride salt. This is in contrast to the known technique, which involves the less efficient method of forming the desired hydrochloride from the free base.
Beskrivelse av oppfinnelsen Description of the invention
Foreliggende oppfinnelse vedrører følgelig fremgangsmåte for fremstilling av optisk anriket bupivacain som omfatter omsetning av bupivacain med et vinsyre-oppløsningsmiddel i et vannblandbart organisk løsningsmiddel, kjennetegnet ved at midlet omfatter 1 til 20% vann. The present invention therefore relates to a method for producing optically enriched bupivacaine which comprises reaction of bupivacaine with a tartaric acid solvent in a water-miscible organic solvent, characterized in that the agent comprises 1 to 20% water.
Den nye fremgansmåten utføres fortrinnsvis i overensstemmelse med alle parametrene angitt ovenfor. I andre sammenhenger kan konvensjonell krystallise-ringsteknologi benyttes. Omsetningen utføres fortrinnsvis ved å benytte en C-i.6-alkanol, så som isopropanol, som det primære reaksjonsløsningsmiddel, men ethvert egnet, vannblandbart organisk løsningsmiddel kan benyttes. The new method is preferably carried out in accordance with all the parameters indicated above. In other contexts, conventional crystallization technology can be used. The reaction is preferably carried out using a C 1-6 alkanol, such as isopropanol, as the primary reaction solvent, but any suitable water-miscible organic solvent may be used.
Denne oppfinnelse utføres bekvemt i forbindelse med en racemiserings-prosess. Levobupivacain og dets antipode, og analoger derav, i fri baseform eller som dets salter, kan racemiseres, som beskrevet i internasjonal patentsøknad nr. PCT/GB95/02247, som del av en effektiv recykliserings-prosess. This invention is conveniently carried out in connection with a racemization process. Levobupivacaine and its antipode, and analogs thereof, in free base form or as its salts, can be racemized, as described in International Patent Application No. PCT/GB95/02247, as part of an efficient recycling process.
Følgende eksempler illustrerer oppfinnelsen. The following examples illustrate the invention.
Eksempel 1 Example 1
Bupivacainhydrokloridmonohydrat (1 kg, 2,916 mol) ble hatt i en separator med vann (5 I) og TBME (5 I). Natriumhydroksydløsning (10 N, 300 ml, 3 mol) ble så tilsatt, og reaksjonsblandingen ble omrørt i 5 min., inntil alle faststoffene var blitt oppløst. Røremaskinen ble stoppet og sjiktene fikk skilles i løpet av 0,5 time. Det vandige sjikt ble fraskilt og det organiske sjikt vasket med vann (2 I). Det organiske sjikt ble hatt i et kar beregnet for atmosfærisk destillasjon. TBME (2,5 I) ble destillert. Isopropanol ble tilsatt og destillasjonen fortsatt inntil all TBME var fjernet. Det totale volum av gjenværende isopropanol skulle være 4200 ml (1 del bupivacainbase : 5 deler isopropanol). Vann (105 ml) og deretter (S,S)-(-)-vinsyre (109 g, 0,73 mol, 0,25 ekv.) ble tilsatt ved 80°C, og blandingen ble omrørt ved 80°C, inntil alle faststoffene var blitt oppløst. Bupivacaine hydrochloride monohydrate (1 kg, 2.916 mol) was placed in a separator with water (5 L) and TBME (5 L). Sodium hydroxide solution (10 N, 300 mL, 3 mol) was then added, and the reaction mixture was stirred for 5 min, until all the solids had dissolved. The mixer was stopped and the layers were allowed to separate within 0.5 hour. The aqueous layer was separated and the organic layer washed with water (2 L). The organic layer was kept in a vessel designed for atmospheric distillation. TBME (2.5 L) was distilled. Isopropanol was added and distillation continued until all TBME was removed. The total volume of remaining isopropanol should be 4200 ml (1 part bupivacaine base : 5 parts isopropanol). Water (105 mL) and then (S,S)-(-)-tartaric acid (109 g, 0.73 mol, 0.25 equiv) were added at 80°C, and the mixture was stirred at 80°C, until all the solids had been dissolved.
Løsningen fikk avkjøles til 20°C under sakte omrøring. Hvis krystallisering ikke hadde startet når temperaturen hadde nådd 65°C, ble løsningen kimsatt. Krystallene ble filtrert fra og vasket to ganger med isopropanol (2 x 500 ml) og deretter tørket under vakuum for å få levobupivacain-(S,S)-tartrat (430 g, 80% utbytte av ønsket diastereomer ved 98% enantiomert overskudd). The solution was allowed to cool to 20°C with slow stirring. If crystallization had not started when the temperature had reached 65°C, the solution was seeded. The crystals were filtered off and washed twice with isopropanol (2 x 500 mL) and then dried under vacuum to give levobupivacaine-(S,S)-tartrate (430 g, 80% yield of desired diastereomer at 98% enantiomeric excess).
Eksempel 2 Example 2
Levobupivacain-(S,S)-tartrat (50 g, 0,069 mol) ble oppslemmet i isopropanol (150 ml) og oppvarmet til 50°C. Hydrogenkloridgass (5 g, 0,14 mol) ble innført. Temperaturen steg til 65°C og faststoffene oppløste seg. Blandingen ble oppvarmet til 80°C for å sikre fullstendig oppløsning. Blandingen ble avkjølt til 5°C og et faststoff krystalliserte seg. Faststoffet ble frafiltrert og vasket med isopropanol (2 x 50 ml) og tørket under vakuum for å få levobupivacainhydroklorid (21,9 g, 40%). Levobupivacaine-(S,S)-tartrate (50 g, 0.069 mol) was slurried in isopropanol (150 mL) and heated to 50°C. Hydrogen chloride gas (5 g, 0.14 mol) was introduced. The temperature rose to 65°C and the solids dissolved. The mixture was heated to 80°C to ensure complete dissolution. The mixture was cooled to 5°C and a solid crystallized. The solid was filtered off and washed with isopropanol (2 x 50 mL) and dried under vacuum to give levobupivacaine hydrochloride (21.9 g, 40%).
Eksempler 3-14 og sammenlignende eksempel A Examples 3-14 and Comparative Example A
For å undersøke hvor kritisk nærvær av vann og de relative mengder av forbindelsene med formel (I) og oppløsningsmiddel er, ble forskjellige sammenlignende forsøk utført. I hvert av forsøkene ble det til racemisk bupivacain fri base (20 g) tilsatt IPA (isopropanol, 5 vol) og den angitte mengde vann. Suspensjonen ble oppvarmet under omrøring. Ved tilnærmet 75°C ble den angitte mengde vinsyre tilsatt. Suspensjonen ble bragt til tilbakeløp. Så snart alt faststoffet var blitt oppløst fikk løsningen avkjøles sakte til romtemperatur. Suspensjonen ble. filtrert og det ble tatt en prøve av den oppnådde kaken. Prøven ble behandlet med vandig NaOH og det enantiomere overskudd av den frigjorte frie base målt ved chiral-HPLC. Kaken ble vasket med IPA (20 ml). Faststoffet ble tørket til konstant vekt i en vakuumovn ved 40-50°C. In order to investigate how critical the presence of water and the relative amounts of the compounds of formula (I) and solvent are, various comparative experiments were carried out. In each of the experiments, IPA (isopropanol, 5 vol) and the specified amount of water were added to racemic bupivacaine free base (20 g). The suspension was heated with stirring. At approximately 75°C, the indicated amount of tartaric acid was added. The suspension was reversed. As soon as all the solid had been dissolved, the solution was allowed to cool slowly to room temperature. The suspension was. filtered and a sample of the cake obtained was taken. The sample was treated with aqueous NaOH and the enantiomeric excess of the liberated free base measured by chiral HPLC. The cake was washed with IPA (20 ml). The solid was dried to constant weight in a vacuum oven at 40-50°C.
Resultatene er satt opp i tabell nedenfor, i grupper på henholdsvis 5 og 4 forsøk (som hvert viser effekten av å variere mengden av vann), og 4 og 3 forsøk (som hvert viser effekten av å variere mengden av oppløsningsmiddel). The results are set out in the table below, in groups of 5 and 4 trials respectively (each showing the effect of varying the amount of water), and 4 and 3 trials (each showing the effect of varying the amount of solvent).
Claims (8)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9421476A GB9421476D0 (en) | 1994-10-25 | 1994-10-25 | Process and salt |
| GBGB9504926.8A GB9504926D0 (en) | 1995-03-10 | 1995-03-10 | Crystallisation |
| PCT/GB1995/002513 WO1996012699A1 (en) | 1994-10-25 | 1995-10-23 | Crystallisation of levobupivacaine and analogues thereof |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO971903D0 NO971903D0 (en) | 1997-04-24 |
| NO971903L NO971903L (en) | 1997-04-24 |
| NO309266B1 true NO309266B1 (en) | 2001-01-08 |
Family
ID=26305863
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO971903A NO309266B1 (en) | 1994-10-25 | 1997-04-24 | Process for the preparation of optically enriched bupivacaine |
Country Status (16)
| Country | Link |
|---|---|
| US (1) | US5994548A (en) |
| EP (1) | EP0788480B1 (en) |
| JP (1) | JP3911545B2 (en) |
| AT (1) | ATE245629T1 (en) |
| AU (1) | AU698637B2 (en) |
| CA (1) | CA2200355C (en) |
| DE (1) | DE69531356T2 (en) |
| DK (1) | DK0788480T3 (en) |
| ES (1) | ES2202375T3 (en) |
| FI (1) | FI117438B (en) |
| HU (1) | HU227420B1 (en) |
| MX (1) | MX9703024A (en) |
| NO (1) | NO309266B1 (en) |
| PL (1) | PL183210B1 (en) |
| PT (1) | PT788480E (en) |
| WO (1) | WO1996012699A1 (en) |
Families Citing this family (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BR0002246A (en) * | 2000-04-06 | 2003-04-15 | Cristalia Prod Quimicos Farm | Process for obtaining the enantiomers of racemic bupivacaine, process for obtaining pharmaceutical compositions based on levobupivacaine: pharmaceutical compositions based on levobupivacaine formulated in basic forms or pharmaceutically acceptable salts and use of pharmaceutical compositions based on levobupivacaine formulated in basic forms or pharmaceutically salts acceptable |
| BRPI0104491B8 (en) * | 2001-10-10 | 2021-05-25 | Cristalia Produtos Quim Farmaceuticos Ltda | n-(2,6-dimethylphenyl)-1-propyl-2-piperidinecarboxamide; process of obtaining the enantiomers; non-racemic mixture of anantiomers and its process of obtaining and pharmaceutical composition. |
| US20040001889A1 (en) | 2002-06-25 | 2004-01-01 | Guohua Chen | Short duration depot formulations |
| SI1575569T1 (en) * | 2002-12-13 | 2010-12-31 | Durect Corp | Oral drug delivery system comprising high viscosity liquid carrier materials |
| US6790267B1 (en) * | 2003-04-24 | 2004-09-14 | Xerox Corporation | Colorant compositions |
| US7094812B2 (en) * | 2003-04-24 | 2006-08-22 | Xerox Corporations | Colorant compositions |
| BRPI0515372B8 (en) | 2004-09-17 | 2021-05-25 | Durect Corp | liquid composition to provide prolonged local anesthesia after administration to an individual, and use of bupivacaine, sucrose acetate isobutyrate and benzyl alcohol |
| US20070027105A1 (en) | 2005-07-26 | 2007-02-01 | Alza Corporation | Peroxide removal from drug delivery vehicle |
| EP2010491A1 (en) * | 2006-04-25 | 2009-01-07 | Disham Pharmaceuticals and Chemicals Ltd. | Ropivacaine hydrochloride anhydrate and the preparation thereof |
| PL2117521T3 (en) | 2006-11-03 | 2012-11-30 | Durect Corp | Transdermal delivery systems comprising bupivacaine |
| AU2008347158B8 (en) | 2007-12-06 | 2013-08-22 | Durect Corporation | Oral pharmaceutical dosage forms |
| PT2234974E (en) * | 2008-01-15 | 2012-05-29 | Pharmathen Sa | Process for the preparation of (s)-1-alkyl-2`,6`-pipecoloxylidide compound |
| US20100260844A1 (en) | 2008-11-03 | 2010-10-14 | Scicinski Jan J | Oral pharmaceutical dosage forms |
| CN103073484B (en) * | 2013-01-28 | 2014-10-22 | 山东诚创医药技术开发有限公司 | Preparation method of mepivacaine and optical enantiomer of mepivacaine |
| US9555113B2 (en) | 2013-03-15 | 2017-01-31 | Durect Corporation | Compositions with a rheological modifier to reduce dissolution variability |
| RU2021114918A (en) * | 2016-12-26 | 2021-07-09 | Целликс Био Прайвет Лимитед | COMPOSITIONS AND METHODS FOR TREATMENT OF CHRONIC PAIN |
| KR20220140711A (en) | 2020-01-13 | 2022-10-18 | 듀렉트 코퍼레이션 | Reduced Impurity Sustained Release Drug Delivery Systems and Related Methods |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE341404B (en) * | 1967-05-18 | 1971-12-27 | Sterling Drug Inc | |
| US4695576A (en) * | 1984-07-09 | 1987-09-22 | Astra Lake Medel Aktiebolag | L-N-n-propylpipecolic acid-2,6-xylidide |
-
1995
- 1995-10-23 CA CA002200355A patent/CA2200355C/en not_active Expired - Lifetime
- 1995-10-23 AT AT95934738T patent/ATE245629T1/en active
- 1995-10-23 WO PCT/GB1995/002513 patent/WO1996012699A1/en active IP Right Grant
- 1995-10-23 HU HU9702372A patent/HU227420B1/en unknown
- 1995-10-23 DK DK95934738T patent/DK0788480T3/en active
- 1995-10-23 PT PT95934738T patent/PT788480E/en unknown
- 1995-10-23 MX MX9703024A patent/MX9703024A/en unknown
- 1995-10-23 ES ES95934738T patent/ES2202375T3/en not_active Expired - Lifetime
- 1995-10-23 EP EP95934738A patent/EP0788480B1/en not_active Expired - Lifetime
- 1995-10-23 PL PL95319829A patent/PL183210B1/en unknown
- 1995-10-23 DE DE69531356T patent/DE69531356T2/en not_active Expired - Lifetime
- 1995-10-23 US US08/849,418 patent/US5994548A/en not_active Expired - Lifetime
- 1995-10-23 AU AU37048/95A patent/AU698637B2/en not_active Expired
- 1995-10-23 JP JP51373896A patent/JP3911545B2/en not_active Expired - Lifetime
-
1997
- 1997-04-22 FI FI971711A patent/FI117438B/en not_active IP Right Cessation
- 1997-04-24 NO NO971903A patent/NO309266B1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| PT788480E (en) | 2003-12-31 |
| JP3911545B2 (en) | 2007-05-09 |
| PL319829A1 (en) | 1997-09-01 |
| HU227420B1 (en) | 2011-05-30 |
| MX9703024A (en) | 1997-10-31 |
| WO1996012699A1 (en) | 1996-05-02 |
| DE69531356T2 (en) | 2004-05-27 |
| NO971903D0 (en) | 1997-04-24 |
| FI971711A (en) | 1997-04-22 |
| NO971903L (en) | 1997-04-24 |
| JPH10507464A (en) | 1998-07-21 |
| PL183210B1 (en) | 2002-06-28 |
| EP0788480B1 (en) | 2003-07-23 |
| HUT77631A (en) | 1998-06-29 |
| FI117438B (en) | 2006-10-13 |
| DK0788480T3 (en) | 2003-09-29 |
| AU3704895A (en) | 1996-05-15 |
| FI971711A0 (en) | 1997-04-22 |
| AU698637B2 (en) | 1998-11-05 |
| ATE245629T1 (en) | 2003-08-15 |
| CA2200355A1 (en) | 1996-05-02 |
| DE69531356D1 (en) | 2003-08-28 |
| US5994548A (en) | 1999-11-30 |
| ES2202375T3 (en) | 2004-04-01 |
| EP0788480A1 (en) | 1997-08-13 |
| CA2200355C (en) | 2007-03-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| NO309266B1 (en) | Process for the preparation of optically enriched bupivacaine | |
| WO2007038277A2 (en) | Resolution of alpha-(phenoxy) phenylacetic acid derivatives with naphthyl-alkylamines | |
| US20060135777A1 (en) | Method for the production of d-threo-2-phenyl-2-piperidine-2-yl acetates | |
| AU696875B2 (en) | New process for the preparation of ropivacaine hydrochloride monohydrate | |
| AU2001278094B2 (en) | Novel crystalline forms of 4-[4-[4-(hydroxydiphenylmethyl)-1-piperindinyl]-1-hydroxybutyl]-alpha, alpha-dimethylbenzene acetic acid and its hydrochloride | |
| JP2011012032A (en) | Method for producing optically active 3-aminopiperidine and production intermediate | |
| DK152752B (en) | METHOD OF PREPARING L-SULPIRIDE | |
| US7897777B2 (en) | Process of enantiomeric resolution of D,L-(±)-threo-methylphenidate | |
| KR100472609B1 (en) | Crystallization of Levo-Bupivacaine and Its Analogs | |
| CN111302996A (en) | Preparation method of high-chiral-purity chloromalastine fumarate | |
| US20200131126A1 (en) | Process for the Separation of Optical Isomers of Racemic 3-Alkylpiperidine-Carboxylic Acid Ethyl Esters | |
| JP4000113B2 (en) | (3S) -3-methoxycarbonyl-4-phenylbutyric acid metal salt and method of use thereof | |
| WO2002068391A1 (en) | Process for resolving racemic mixtures of piperidine derivatives | |
| WO2021166934A1 (en) | Production method for pyrrolidine compound | |
| US20040039206A1 (en) | Process for resolving racemic mixtures of piperidine derivatives | |
| CN117510398A (en) | Preparation method of (3R, 4R)/(3S, 4S) -N-BOC-4-amino-3-hydroxy piperidine with high optical purity | |
| WO2010079605A1 (en) | Process for producing high-purity 1-benzyl-3-aminopyrrolidine | |
| WO2000039090A1 (en) | Process for the preparation of paroxetine acetate and analogues thereof | |
| WO2000039121A1 (en) | Process for the preparation of an acetate salt of paroxetine or paroxetine analogues | |
| EP1140911A1 (en) | Process for the preparation of an acetate salt of paroxetine or paroxetine analogues | |
| JPH0687828A (en) | Synthesis of difluoromethyl compound by cyclization | |
| EP1140912A1 (en) | Process for the preparation of an acetate salt of paroxetine or paroxetine analogues |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MK1K | Patent expired |